Mupirocin is an antimicrobial agent that inhibits bacterial isoleucyl-tRNA synthetase mediated Ile-tRNA aminoacylation and, consequently protein translation. See Hughes J, Mellows G., “On the mode of action of pseudomonic acid: inhibition of protein synthesis in Staphylococcus aureus,” The Journal of Antibiotics, 31:330-335 (1978); Hughes J, Mellows G., “Inhibition of isoleucyl-transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid,” The Biochemical Journal 176:305-318 (1978); Hughes J, Mellows G., “Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase,” The Biochemical Journal 191:209-219 (1980). The agent displays excellent antibacterial activity toward most Gram-positive species, lacks cross resistance to current antibiotics and is well absorbed in humans but is also rapidly degraded in vivo, and consequently is not ideal for systemic use. See Sutherland R, Boon R J, Griffin K E, Masters P J, Slocombe B, White A R., “Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use,” Antimicrob Agents Chemother 27:495-498 (1985). However, mupirocin based ointments have proven effective for the treatment of S. aureus skin and wound infections and have also recently emerged as the standard of care for pre-surgical nasal decolonization. See Beale A S, Gisby J, Sutherland R., “Efficacy of mupirocin calcium ointment in the treatment of experimental wound infections caused by methicillin-resistant strains of Staphylococcus aureus,” Journal of Chemotherapy (Florence, Italy) 1:397-398 (1989); Moy J A, Caldwell-Brown D, Lin A N, Pappa K A, Carter D M., “Mupirocin-resistant Staphylococcus aureus after long-term treatment of patients with epidermolysis bullosa, Journal of the American Academy of Dermatology 22:893-895 (1990); Rode H, de Wet P M, Millar A J, Cywes S., “Bactericidal efficacy of mupirocin in multi-antibiotic resistant Staphylococcus aureus burn wound infection, The Journal of Antimicrobial Chemotherapy 21:589-595 (1988); Rode H, Hanslo D, de Wet P M, Millar A J, Cywes S., “Efficacy of mupirocin in methicillin-resistant Staphylococcus aureus burn wound infection,” Antimicrob Agents Chemother 33:1358-1361(1989); Coates T, Bax R, Coates A., “Nasal decolonization of Staphylococcus aureus with mupirocin: strengths, weaknesses and future prospects,” The Journal of Antimicrobial Chemotherapy 64:9-15 (2009). Indeed, mupirocin mediated nasal decolonization has been shown to be effective in reducing burn wound infections, pulmonary infections, infections in dialysis patients, surgical site infections, orthopedic infections, and S. aureus transmission among healthcare workers and intensive care unit patients. See Mupirocin Study Group, “Nasal mupirocin prevents Staphylococcus aureus exit-site infection during peritoneal dialysis,” Journal of the American Society of Nephrology: JASN 7:2403-2408 (1996); Gaspar M C, Uribe P, Sanchez P, Coello R, Cruzet F., “Hospital personnel who are nasal carriers of methicillin-resistant Staphylococcus aureus, Usefulness of treatment with mupirocin,” Enfermedades Infecciosasy Microbiologia Clinica 10:107-110 (1992); Gernaat-van der Sluis A J, Hoogenboom-Verdegaal A M, Edixhoven P J, Spies-van Rooijen N H., “Prophylactic mupirocin could reduce orthopedic wound infections. 1,044 patients treated with mupirocin compared with 1,260 historical controls,” Acta Orthopaedica Scandinavica 69:412-414(1998); Kluytmans J A, Mouton J W, VandenBergh M F, Manders M J, Maat A P, Wagenvoort J H, Michel M F, Verbrugh H A., “Reduction of surgical-site infections in cardiothoracic surgery by elimination of nasal carriage of Staphylococcus aureus,” Infection Control and Hospital Epidemiology: the official journal of the Society of Hospital Epidemiologists of America 17:780-785 (1996); Mackie D P, van Hertum W A, Schumburg T H, Kuijper E C, Knape P, Massaro F., “Reduction in Staphylococcus aureus wound colonization using nasal mupirocin and selective decontamination of the digestive tract in extensive burns,” Burns: Journal of the International Society for Burn Injuries 20 Suppl 1:S14-17; discussion S17-18 (1994); Talon D, Rouget C, Cailleaux V, Bailly P, Thouverez M, Barale F, Michel-Briand Y., “Nasal carriage of Staphylococcus aureus and cross-contamination in a surgical intensive care unit: efficacy of mupirocin ointment,” The Journal of Hospital Infection 30:39-49 (1995); Wenisch C, Laferl H, Szell M, Smolle K H, Grisold A, Bertha G, Krause R., “A holistic approach to MRSA eradication in critically ill patients with MRSA pneumonia,” Infection 34:148-154 (2006). However, the emergence of S. aureus mupirocin resistance has reduced the agent's efficacy both as a nasal decolonization agent and as a treatment option for skin and wound infections.
Low level mupirocin resistant S. aureus strains are commonly defined as exhibiting an MIC of 8 to ≤256 μg ml−1 due to point mutations in the organism's native isoleucyl tRNA synthetase gene (ileRS) and develop rapidly in both the laboratory and clinical setting. See Lee A S, Gizard Y, Empel J, Bonetti E J, Harbarth S, Francois P., “Mupirocin-induced mutations in ileS in various genetic backgrounds of methicillin-resistant Staphylococcus aureus,” J Clin Microbiol 52:3749-3754 (2014); High level mupirocin resistance (MIC of >512 mg/L) occurs less frequently and is attributable to the acquisition of a mobile genetic elements harboring either mupA, which codes for an alternate isolecyl tRNA synthetase, or the less-characterized mupB gene. See Fierobe L, Decre D, Muller C, Lucet J C, Marmuse J P, Mantz J, Desmonts J M., “Methicillin-resistant Staphylococcus aureus as a causative agent of postoperative intra-abdominal infection: relation to nasal colonization,” Clin Infect Dis 29:1231-1238 (1999); Seah C, Alexander D C, Louie L, Simor A, Low D E, Longtin J, Melano R G., “MupB, a new high-level mupirocin resistance mechanism in Staphylococcus aureus,” Antimicrob Agents Chemother 56:1916-1920 (2012). Indeed, a retrospective survey of methicillin resistant S. aureus (MRSA) nasal and blood isolates collected from 23 U.S. hospitals revealed that 3% and 5% isolates tested displayed high level mupirocin resistance, respectively, whereas single hospital low level mupirocin resistance ranges from 0% to 80%. See Hetem D J, Bonten M I, “Clinical relevance of mupirocin resistance in Staphylococcus aureus,” The Journal of Hospital Infection 85:249-256 (2013). Thus, while mupirocin has proven an effective means of mediating S. aureus decolonization and reducing infection, mupriocin resistance has prompted renewed interest in developing alternative decolonization and wound infection treatment strategies.
S. aureus RNase P is an essential riboprotein complex consisting of RnpA and ribozyme rnpB that acts upstream of tRNA synthetases in the transfer RNA maturation pathway. More specifically RNase P catalyzes removal of the 5′ leader sequences from precursor tRNA species creating mature tRNA substrates for tRNA synthetases including isoleucyl tRNA synthetase (the cellular target for mupirocin). Recognizing that two antimicrobials targeting independent steps of the same bacterial metabolic pathway can have combined antibacterial effects it has been hypothesized that combination therapies involving mixtures of RNase P inhibitors together with mupirocin would display increased antimicrobial efficacy and the potential to overcome mupirocin resistance. However, combining RNase P inhibitors with tRNA synthetase inhibitors for treating a bacterial infection or inhibiting bacterial growth has not consistently shown synergistic therapeutic effects in vitro, and so far none of the known combination therapies using the compounds from these two categories has shown in vivo synergistic effects in treating bacterial infections or inhibiting bacterial growth.